Autonomously growing implantable device

ABSTRACT

An implantable, autonomously growing medical device is disclosed. The device may have an outer, braided outer element that holds an inner core. Degradation and/or softening of the inner core permits the outer element to elongate, allowing the device to grow with surrounding tissue. The growth profile of the medical device can be controlled by altering the shape/material/cure conditions of the inner core, as well as the geometry of the outer element.

RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application Ser. No. 62/295,768, entitled “AUTONOMOUSLYGROWING IMPLANTABLE DEVICE” filed on Feb. 16, 2016, the entire contentsof which are incorporated herein by reference.

BACKGROUND 1. Field

Aspects described herein relate generally to an autonomously growingimplantable device.

2. Discussion of Related Art

Conventional medical devices used to treat anatomic and morphologicdefects are fixed in size. Biodegradable annuloplasty rings that havebeen developed for use in children provide temporary annular supportuntil they completely degrade.

SUMMARY

In an illustrative embodiment, an implantable device is provided. Theimplantable device includes an outer element having a first length. Thedevice also includes an inner core disposed within the outer element.Presence of the inner core limits elongation of the outer element.Degradation of the inner core permits elongation of the outer elementfrom the first length to a second length that is longer than the firstlength.

In another illustrative embodiment, a method of using an implantabledevice is provided. The method includes providing an outer element withan inner core disposed within the outer element. The method alsoincludes coupling the outer element to an implantation site. Contactingthe inner core with body fluid at the implantation site initiatesdegradation of the inner core. Degradation of the inner core permitselongation of the outer element from a first length to a second lengththat is longer than the first length. The length of the outer elementchanges from the first length to the second length in response todegradation of the inner core and to forces from native growing tissueat the implantation site acting on the outer element.

In yet another illustrative embodiment, a method of forming abiodegradable polymer is provided. The method includes polycondensationof an equimolar ratio of glycerol and sebacic acid at 120° C. for 8hours under dry nitrogen and for 16 hours in vacuum to form apre-polymer. The method also includes curing the pre-polymer in a vacuumat a temperature of 140° C. to 160° C. for 40 to 100 hours.

In yet another illustrative embodiment, a polymer is provided. Thepolymer has a Young's Modulus of greater than 5 MPa and a crosslinkingdensity of 600 to 12,000 mols per cubic meter. The polymer is formedfrom curing a poly(glycerol sebacate) pre-polymer in vacuum at atemperature of 140° C. to 160° C. for 40 to 100 hours.

Various embodiments provide certain advantages. Not all embodiments ofthe present disclosure share the same advantages and those that do maynot share them under all circumstances.

Further features and advantages of the present disclosure, as well asthe structure of various embodiments are described in detail below withreference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments will now be described, by way of example, withreference to the accompanying drawings, in which:

FIG. 1A depicts a schematic representation of an embodiment of animplantable device in accordance with one aspect;

FIG. 1B depicts a schematic representation of the implantable device ofFIG. 1A exhibiting growth in one dimension;

FIG. 2A depicts an embodiment of an implantable device in accordancewith one aspect;

FIG. 2B depicts the implantable device of FIG. 2A exhibiting growth inone dimension;

FIG. 3A depicts a schematic representation of another embodiment of animplantable device in accordance with one aspect;

FIG. 3B depicts a schematic representation of the implantable device ofFIG. 3A exhibiting growth in two dimensions;

FIG. 4A depicts an embodiment of an implantable device used in a heartvalve annuloplasty application in accordance with one aspect;

FIG. 4B depicts a schematic representation of the implantable device ofFIG. 4A exhibiting growth in two dimensions;

FIG. 5 depicts a graph showing the relationship between outer elementbehavior and inner core degradation;

FIG. 6 depicts data from an ex vivo demonstration of controlled valvegrowth using an autonomously growing implantable device;

FIG. 7 depicts a graph showing different polymer degradation ratesresulting from different curing conditions;

FIG. 8 depicts a graph showing varying Young's moduli resulting fromdifferent polymer curing times;

FIG. 9 depicts an embodiment of an implantable device in accordance withone aspect;

FIG. 10 depicts a graph showing the relationship between outer elementlength and outer element diameter at different braid pitches;

FIG. 11 depicts a graph comparing experimentally measured outer elementlengths to values predicted from a mathematical model;

FIG. 12 depicts a graph showing the results of cyclic tensile testing onan implantable device in accordance with one aspect;

FIG. 13A is a cartoon depicting to types of device implants on a growingtibia;

FIG. 13B shows micro-CT images in axial (left) and sagittal (right)cross-section of the fixed-size device at post-op and at 8 weeks afterimplantation;

FIG. 13C is a side-by-side comparison of the fixed-size device atimplant (left) and explant (right);

FIG. 13D shows micro-CT images in axial (left) and sagittal (right)cross-section of the growing device at post-op and at 8 weeks afterimplantation;

FIG. 13E is a side-by-side comparison of the growing device at implant(left) and explant (right);

FIG. 13F is a graph comparing growth of the right tibia, the growingdevice left tibia and the fixed device left tibia;

FIG. 13G is a graph comparing predicted growth and observed devicegrowth;

FIG. 14A is an image of a fixed-size annuloplasty device used in adults;

FIG. 14B is a photograph of a UHMWPE biaxially braided sleeve placedover a pre-curved cylindrical ESPGS polymer core;

FIG. 14C is a photograph showing the braid pattern of the biaxiallybraided sleeve;

FIG. 14D is a photograph of an ex vivo demonstration of ringimplantation with en face view of the tricuspid valve;

FIG. 14E is a photograph of an en face view of the freshly explantedtricuspid valve and ring 12 weeks after surgery;

FIG. 14F depicts a cross-section through the explanted ring showing acollagen layer that grew over the growing device;

FIG. 14G depicts photographs of explanted ESPGS samples showing erosionat the surface of the polymer;

FIG. 14H depicts cross-sections through segments of the ring/annulus;

FIG. 14I depicts a graph of the annular area of the valve at three timepoints during the study: pre-implant, post-implant, and euthanasia.

DETAILED DESCRIPTION

Over 400,000 surgeries are performed annually on children in the UnitedStates to correct anatomic and morphologic defects. Medical implantsthat can respond to and guide tissue growth represent a longstandingunmet clinical need, especially for use in the treatment of pediatricsurgical conditions. The inventors have recognized that existing deviceimplants that have a fixed size have limited application in growingchildren. Use of fixed-size implants in children leads to growthrestriction and requires eventual device removal, subjecting children torepeated surgical procedures and increased complication rates.

In some cases, such as pediatric heart valve surgery, fixed-sizeimplants are avoided due to the deleterious effects of growthrestriction on the heart. While prosthetic implants have greatlyimproved the durability of surgical repair in adults, the lack ofgrowing implants for children has led to poorer outcomes. Currentlyavailable prosthetic rings, which are implanted on the annulus ofdilated heart valves, may not, in some circumstances, be suitable foruse in children, because the fixed size of the rings may restrict normalvalve growth and may cause stenosis over time. Another available deviceis a biodegradable annuloplasty ring, which provides temporary annularsupport until it completely degrades. Given that the biodegradable ringinevitably loses mechanical integrity, such a device may be subject tomechanical failure.

As a result, pediatric heart surgeons often rely on suture-basedannuloplasty techniques. In such techniques, the repair sutures break orpull through the tissue over time allowing for valve growth. However,this stretching and loss of tissue anchoring is unpredictable andpredisposes patients to pathologic re-dilation of the valve andrecurrence of valve dysfunction. The lack of a suitable prostheticdevice that can grow with a growing patient to provide ongoing annularsupport is one reason pediatric heart repair outcomes lag behind thoseof adults. Over 80% of adult tricuspid valve repairs using a prostheticring do not have recurrent valve dysfunction or re-operation 15 yearsafter surgery. In contrast, successful valve repair is achieved in only50% of children with single-ventricle anatomy, and failed repair is anindependent risk factor for mortality.

Pediatric orthopedic disorders involving abnormal long-bone growth (e.g.limb-length discrepancy and angular limb deformities) were historicallytreated with invasive surgical osteotomies to provide immediate skeletalcorrection. These surgeries carried significant morbidity, includingpost-operative pain, requisite activity restriction, and nerve andvascular injury. Recently, techniques using internal fixators (e.g.staples and plated systems) implanted across the growth plate have beenadopted, which are less morbid and enable more gradual repair ofskeletal deformities. Unfortunately, the existing fixed-size implantsmust be removed after deformity correction to prevent excessive growthrestriction, thus subjecting children to additional surgical procedures.Moreover, after device removal, children are at risk for rebound growth,recurrent limb deformation, and need for repeated surgicalinterventions.

Surgical correction of scoliosis has similar limitations. Traditionalsurgical repair techniques involved spinal fusion procedures, whichimpeded spinal growth and led to pulmonary insufficiency in children.More recently, “growing” rod systems have been developed and are acommon surgical repair technique. While the growing rod system permitsongoing spinal and thoracic growth, the implantable device does notautonomously grow. Frequent interventions are required to lengthen therods, with some children requiring as many as fifteen surgicalprocedures. Complication rates approach 60%, and each surgery increasesthe likelihood of a child experiencing a complication by 24%.

Accordingly, the inventors have recognized a need for medical devicesthat can grow autonomously to enable more durable surgical repairs andto eliminate the need for repeated surgical interventions in growingpatients, particularly in children.

Described herein is an autonomously growing implantable device forsupporting tissue to correct anatomic and morphologic defects. Thedevice can, in some embodiments, be used for pediatric applications.

The device comprises a unique form of an inner core located inside anouter element that surrounds the inner core. The outer element isconfigured such that a decrease in width or diameter of the outerelement results in an increase in length of the outer element, and viceversa. Described another way, in some embodiments, the outer element isconfigured such that an increase in one dimension of the outer elementresults in a decrease in a second dimension of the outer element andvice versa, the second dimension being perpendicular to the firstdimension.

In some embodiments, the outer element is shaped in a tubular sleeve.However, it should be appreciated that other arrangements of the outerelement are possible, such as a sleeve with a rectangular, square,triangular or other cross section, a spherical or ellipsoidal shape, orother suitable shape that surrounds the inner core, where change indiameter or width of the outer element results in change in length ofthe outer element, and vice versa.

The presence of the inner core inside the outer element limits thelength of the outer element by preventing the outer element fromelongating. As the inner core gradually degrades and/or softensfollowing surgical implantation of the device, the outer element ispermitted to gradually elongate to accommodate native tissue growth. Thedevice is designed to initially restrict growth/expansion of the nativetissue to which the device is coupled, but as the inner core degradesand/or softens over time, the device may grow at a pre-determined rateto guide tissue growth. The growth profile of the device may becustomizable by adjusting one or more features of the device.

In some embodiments, an implantable device is configured to undergogrowth in one dimension (i.e., elongation). FIGS. 1A-1B depict schematicrepresentations of an embodiment of an implantable device exhibitinggrowth in one dimension. Implantable device 1 includes an outer element30 and an inner core 10 (the inner core is outlined in dot-dash-dotlines). In some embodiments, such as the one shown in FIGS. 1A-1B, theouter element takes the shape of a tubular sleeve. In the first stage,shown in FIG. 1A, the presence of the inner core 10 sets the diameter ofthe sleeve 30, and prohibits the sleeve 30 from lengthening, even whensubject to external forces F.

The outer element is coupled to the native growing tissue located at theimplantation site (e.g. bone, cardiac tissue, etc.). As the tissue atthe implantation site grows (e.g. bone lengthening, heart valve annulusexpanding, etc.), the growing tissue, which is coupled to the outerelement of the implantable device, generates a force F that acts on theouter element.

As the inner core 10 degrades and/or softens, the diameter of the outerelement 30 is permitted to decrease. Due to the external forces Fapplied on the outer element 30 by the growing native tissue, thediameter of the outer element 30 decreases and the outer elementelongates, resulting in the second stage, in which the device has grownin length, shown in FIG. 1B.

FIGS. 2A-2B depict an embodiment of an implantable device used forapplications in which growth in only one dimension is desirable, such aslong-bone orthopedic applications. Gradual degradation and/or softeningof the inner core 10 permits gradual decrease in the diameter of theouter element 30, and concomitant device elongation in one dimension inresponse to applied external forces pulling on the ends of the outerelement. As seen when comparing FIG. 2A to FIG. 2B, the distance betweenthe first end 101 of the implantable device 1 and the second end 102 ofthe implantable device increases as the inner core 10 degrades and/orsoftens.

In some embodiments, an implantable device is configured to undergogrowth in two dimensions while the diameter of the device decreases.Described another way, with devices that are not straight, as theoverall length of the device increases, the device expands in twodimensions while the diameter of the device decreases. In the case of aring-shaped or curved/bent band device, growing in two dimensions meansthat the area circumscribed by the ring-shaped or curved/bent banddevice increases.

FIGS. 3A-3B depict schematic representations of an embodiment of animplantable device exhibiting growth in two dimensions. Implantabledevice 1 includes a curved outer element 30 and an inner core 10. In thefirst stage, shown in FIG. 3A, the presence of the inner core 10 setsthe diameter of the outer element 30, and prohibits the outer element 30from elongating, even when subject to the external forces F generatedfrom native growing tissue at the site of implantation. As the innercore 10 degrades and/or softens, the diameter of the outer element 30 ispermitted to decrease. As the diameter of the outer element 30decreases, the outer element elongates in reaction to external forces F,resulting in the second stage, where the device has grown in twodimensions, shown in FIG. 3B.

Implantable devices that are configured to undergo growth in twodimensions can serve as autonomously growing heart valve annuloplastydevices such as rings or curved/bent bands. FIGS. 4A-4B depict anembodiment of an implantable device used for heart valve annuloplastyapplications. The device is configured to grow in two dimensions.Gradual degradation and/or softening of the inner core 10 leads togradual decrease in the diameter of the outer element 30 and concomitantgrowth in two dimensions. As seen when comparing FIG. 4A to 4B, thelength of the implantable device increases as the inner core 10 degradesand/or softens. Said another way, the device, which is in the form of anannuloplasty device, expands in two dimensions as the inner core 10degrades and/or softens. In FIGS. 4A and 4B, the drawn outline 11 is notpart of the implantable device; it is an outline of the areacircumscribed by the annuloplasty band device, and also represents theoutline of the valve orifice. This outline 11 shows that expansion ofthe annuloplasty band permits expansion of the valve orifice.

As discussed above, the implantable device is configured such thatdegradation of the inner core leads to gradual decrease in the innercore diameter/size, which allows the outer element to increase inlength. One example of the relationship between the outer elementbehavior and inner core degradation is shown in the graph depicted inFIG. 5. The graph illustrates that inner core degradation permitsbraided outer element elongation and gradual ring/band expansion. Itshould be noted that the graph depicted in FIG. 5, along with FIGS. 6and 7, reflect the results of accelerated degradation studies. It iscontemplated that actual implantable devices to be used in humanpatients would degrade and/or soften over longer periods of time, e.g.,months or years.

The implantable device described herein can be used to initiallyrestrict tissue growth, and then gradually support and guide tissuegrowth along a predetermined profile. FIG. 6 depicts data from an exvivo demonstration of controlled valve growth using an autonomouslygrowing implantable device with degradable cores. The initial valve areawas 877.2±141.2 mm². With device implantation, the valve area reduced to650.6±55.3 mm² (25% reduction). Due to degradation of the core, thedevice could elongate, leading to controlled heart valve area growth tothe target valve area of 780 mm² (20% growth). This study demonstratesthat an implantable device can be used to initially reduce the size ofthe native tissue at the implantation site and/or restrict growth ofnative tissue, and then gradually guide the growth of the tissue overtime as the inner core of the device degrades and/or softens.

The Inner Core

The inner core can be made from a material that changes in reaction tocontact with body fluids. The inner core may be biodegradable, and/or itmay be a material that becomes softer over time when placed in contactwith body fluids.

In some embodiments, the inner core is made of a polymer, such as amodified polymer poly(glycerol sebacate) (PGS), hereinafter referred toas “extra-strong PGS” or “ESPGS.” In some embodiments, ESPGS can besynthesized using reaction conditions that achieve increasedcrosslinking between polymers. In some cases, synthesis of ESPGS occursin vacuum within polytetrafluoroethylene (PTFE) cylindrical molds.Different curing conditions for ESPGS are possible, and changes incuring conditions give rise to differences in various properties such asdegradation rates and the Young's modulus of the polymer. As such,certain curing conditions can be chosen to achieve a desired degradationrate and/or a desired Young's modulus. In one example, to make ESPGS, aviscous PGS pre-polymer was synthesized via catalyst-free, solvent-freepolycondensation of 0.1 mol each of glycerol and sebacic acid (or otherequimolar ratio) at 120° C. for 8 hours in a nitrogen environment (e.g.,under dry nitrogen) and for 16 hours in vacuum. The resultant viscouspre-polymer was then injected into thin-walled PTFE tubing (innerdiameter=1.8 mm), which acted as a sacrificial mold. The PGS pre-polymermay then be cured in vacuum (e.g., in a vacuum oven) at 140° C. to 160°C. for 40 to 100 hours. In one embodiment, after being injected into thePTFE tubing, the PGS pre-polymer is cured in a vacuum oven at 155° C.for 86 hours, resulting in 1.8 mm ESPGS cylinders.

In some embodiments, prior to degradation, ESPGS limits stretching of adevice to less than 5%.

The PGS pre-polymer may be cured at different temperatures to formESPGS. In some embodiments, the PGS pre-polymer is cured at atemperature of 120-140° C., 125-135° C., 128-132° C. or 130° C. In otherembodiments, the PGS pre-polymer is cured at a temperature of 145-165°C., 150-160° C., 153-157° C. or 155° C.

The PGS pre-polymer may also be cured for different lengths of time toform ESPGS. In some embodiments, the PGS pre-polymer is cured for 40-100hours, 70-100 hours, 80-90 hours, 84-88 hours, at 86 hours. In otherembodiments, the PGS pre-polymer is cured for 30-65 hours, 45-55 hours,46-50 hours, or at 48 hours.

For example, in some embodiments, the PGS pre-polymer is cured at 155°C. for 86 hours or for 48 hours. In some embodiments, the PGSpre-polymer is cured at 130° C. for 86 hours or for 48 hours. In someembodiments, the PGS pre-polymer is cured at a temperature of over 150°C. for over 80 hours.

In some embodiments, the curing duration and temperature can be variedbased on clinical application to achieve device elongation profiles thatspan from months to years.

FIG. 7 depicts a graph showing different ESPGS degradation rates fordifferent polymer curing conditions in accelerated degradation studiesusing a strong base (0.1 M NaOH solution in water, pH 13.0). FIG. 7shows that using a higher cure temperature of 155° C. leads to slowerdegradation rates as compared to a lower cure temperature of 130° C. Assuch, in some cases, if slower degradation rate is desired, a highercure temperature may be a suitable choice, and if a faster degradationrate is desired, a lower cure temperature may be a suitable choice. Asshown in FIG. 7, the degradation rate of ESPGS was 9.2-fold slower thanthat of conventional PGS, suggesting that complete degradation of ESPGSin physiological conditions could be adjusted depending upon theclinical application. In some embodiments, when kept in a NaOH solutionin water having a pH of 13.0, the ESPGS degradation rate ranges from0.05 to 1.0 mm/week.

The inventors have also appreciated that different cure conditionsresult in different Young's moduli. FIG. 8 depicts a graph showingdifferent Young's moduli resulting from different polymer curing times.FIG. 8 shows that using a longer cure time results in a higher Young'smodulus. When the PGS pre-polymer was cured for 86 hours at 155° C., theYoung's modulus for the resulting ESPGS reached 173 MPa. This greatlyexceeded the compressive modulus of conventional PGS and also surpassedthe Young's modulus of commercially available surgical sutures (e.g.PTFE and polydioxanone (PDS)).

In one embodiment, when the PGS pre-polymer was cured for 100 hours at160° C., the Young's modulus for the resulting ESPGS was 200 MPa.

In some embodiments, the curing temperature and duration of the PGSpre-polymer when forming ESPGS can be varied based on clinicalapplication to achieve a Young's Modulus of 100 to 200 MPa.

Mechanical testing was performed on an ADMET eXpert 7601 universaltester, equipped with a 50 N load cell and using the device with acylindrical ESPGS core (length: 10 mm, diameter: 1.8 mm) and an outerUHMWPE braided sleeve. Uniaxial tensile testing was performed at a jograte of 10 mm/min until sample failure (n>3 per condition), and Young'smodulus was calculated as the slope at 20% strain. ESPGS cores cured for24, 42, 62, or 86 hours were compared to evaluate the effect of polymercore mechanical strength on the overall tensile strength of the device.

The inventors have also appreciated that different cure conditionsresult in different crosslinking properties. In some embodiments, thecrosslinking density of ESPGS ranges from 600 to 12,000 mol/m³.

It should be appreciated that the inner core can be formed intodifferent shapes, and that the shape of the inner core may impactdegradation rate of the core. In some cases, an increase in the core'ssurface-area-to-volume ratio will increase the degradation rate. In someembodiments, the inner core has a cylindrical shape. In otherembodiments, the inner core may have a spherical shape, or may be arectangular, square or triangular prism. In yet other embodiments, theinner core may be crescent-shaped, may be a curved arc or may be anirregular shape. In addition, the inner core may be a single piece, ormay be a collection of a plurality of pieces. For example, the innercore may be a single rod-like piece. Alternatively, the inner core maybe formed of a collection of small rods or cylinders.

In one illustrative embodiment shown in FIG. 9, the inner core 10 isformed of a plurality of separate spheres that are held together by theouter element 30. Alternatively, in other embodiments, the inner core isformed as a single piece of material that extends through the outerelement.

It should be appreciated that the inner core may be made of materialsother than polymer. For example, the inner core may be made of one ormore metals that undergo erosion in vivo, or other material thatundergoes erosion or other degradation in vivo. In some embodiments, theinner core need not be biodegradable. Instead, the material the innercore may become softer overtime. For example, in some embodiments, theinner core is made of a swellable material that takes up water or otherliquid over time and become softer, such as polyacrylic acid.

The Outer Element

The outer element is configured to elongate in one or more dimensions inreaction to external forces. In some embodiments, the outer element isin the form of a braided element. In some embodiments, such as in theillustrative embodiments shown in FIGS. 1-5, the outer element is in theform of a biaxial braid.

The growth profile of the device can be controlled in part using thegeometry of the outer element. In the case of an outer element that isshaped as a tubular sleeve, the inventors have developed a mathematicalmodel to describe the growth profile of the autonomously growing deviceas a function of the sleeve geometry. Sleeve parameters affecting thegrowth profile of the implantable device include: initial sleeve length(L_(i)), initial sleeve diameter (D_(i)), instantaneous sleeve diameter(D), and pitch (i.e. number of fiber turns, n, per unit length). Withthese inputs, instantaneous sleeve length (L) can be defined as afunction of instantaneous sleeve diameter (D) as shown in the equationbelow:

L(D)=√{square root over ((πnD _(i))² +L _(i) ²−(πnD)²)}  Equation 1

Instantaneous sleeve length is the length of the sleeve at a specificpoint in time, and instantaneous sleeve diameter is the diameter of thesleeve at that same specific point in time. Considering that the size ofthe inner core determines the instantaneous sleeve diameter, and thatinitial sleeve length is determined by the desired initial device size,the braid pitch is an important parameter of the sleeve for controllingthe growth profile. Adjusting braid pitch allows for the creation of arange of unique braid elongation profiles.

According to the mathematical model, devices with higher pitchdemonstrate greater length change for a given diameter change of theouter element. FIG. 10 depicts the relationship between outer elementlength (expressed as percent growth) and outer element diameter atdifferent braid pitches. The percent growth of the outer element lengthis inversely related to outer element diameter. Leaving other braidparameters constant, by increasing braid pitch (which can be defined bypicks-per-inch (ppi)) from 46 ppi to 54 ppi to 60, a greater outerelement elongation can be achieved. In one illustrative embodiment, anouter element with a 2 mm initial diameter (D₁) and pitches of 46, 54,and 60 ppi (picks-per-inch) can grow up to 38.4%, 50.6%, and 62.8%,respectively, when the inner core is fully degraded (FIG. 10). Thisindicates that the device's growth profile can be adjusted to fitdifferent pediatric surgical applications or projected growth profiles.

The outer element can be configured to have different growth ranges. Insome embodiments, the outer element can be configured to accommodate allof growth from infancy to adulthood such that the outer element can beimplanted in infancy and grow with the patient into adulthood. In otherembodiments, the device may be implanted in an older child, in whichcase the required amount of growth will likely be less. In someembodiments, the outer element may have a growth range of 10% to 180%,100% to 180%, 150% to 180%, or 160% to 180%.

In some embodiments, an implantable device has a biaxially braided outerelement having a pitch of 46 ppi (picks per inch), 54 ppi, or 60 ppi. Inother embodiments, the outer element may have a pitch of 20 to 70 ppi.However, it should be understood that the outer element may employ othersuitable pitches to adjust the growth profile of the implantable device.

In some embodiments, the initial device diameter (D_(i)) and initialdevice length (L₁) can be modified so that the braided outer elementstarts in a more shortened state. In this shortened state, the braidedouter element's elongation capacity is increased (e.g., 180%) and canaccommodate the aforementioned growth range.

The device growth profile is not only tunable, it is predictable aswell. As shown in FIG. 11, experimentally measured outer elementlengths, represented by the dots, correlated well with the predictedvalues from the mathematical model, which is represented by the curves(R²>0.99).

In addition, the implantable device holds up well against fatiguetesting. The implantable device was subjected to cyclic tensile testing.As shown in FIG. 12, cyclic tensile testing demonstrates no evidence ofdevice fatigue following 1000 cycles. Cyclical fatigue tensile testing(n=3) was performed at a jog rate of 50 mm/min, by sample extensionuntil 30% elongation during 1000 consecutive cycles. Stress-straincurves were recorded every 100 cycles.

While the outer element may be a biaxial braid in some embodiments, itshould be appreciated that other braid configurations are possible, suchas a triaxial braid. In some embodiments, the strands of the braidedouter element can themselves be braided, so that the braid strandselongate in addition to the overall outer element construct.

According to one aspect, the number and thickness of braid fibers couldbe reduced to create a “looser” braid that would allow greater access ofwater molecules to the polymer core and facilitate continued polymerdegradation.

It should be appreciated that the outer element may be made of anysuitable material. In some embodiments, the outer element is made ofultra-high-molecular-weight polyethylene (UHMWPE). Other materials suchas polytetrafluoroethylene (PTFE), ethylene chlorotrifluoroethylene(ECTFE) and nitinol are also contemplated.

Assembly of the Device and Implantation

After the inner core is created and shaped, the inner core is insertedinto the outer element. The outer element may be initially open on oneor both ends to receive the inner core. After the inner core is insertedinto the outer element, the one or more open ends of the outer elementare closed by, for example, adhesive, suture or otherstring/thread/wrapping element used to tie the end(s) closed, mechanicalfasteners, or any other suitable means. Alternatively, the outer elementbegins as a flat sheet that is wrapped around the inner core, and theouter element is then held closed by any suitable means such as thosementioned above.

In some embodiments, with the inner core disposed within the outerelement, the outer element is initially pulled taut to tighten the outerelement about the inner core.

Once assembled, the device is inserted into the implantation site andcoupled to tissue located at the implantation site. The device may becoupled to tissue via suture, mechanical fasteners, adhesive, or anyother suitable means. In some embodiments, sutures are looped throughand/or tied to the outer element and then passed through tissue locatedat the implantation site to couple the outer element of the device tothe tissue. As the tissue at the implantation site grows with thepatient, the tissue exerts a force on the outer element of the device.Initially, the presence of the inner core within the outer elementlimits the outer element from elongating or otherwise growing with thetissue. As the inner core begins to degrade and/or soften over time, theouter element is permitted to elongate in the direction(s) of theforce(s) exerted by the tissue. Such elongation may occur in one or moredimensions.

Example 1: Implantable Device Exhibiting Growth in One Dimension

In some embodiments, the device can be used to guide growth in onedimension, e.g. to treat abnormal long-bone growth. As an example ofgrowth in one dimension, the growth of the device and its effect on bonegrowth were evaluated in a growing rat model. Young, growing male Wistarrats (150-200 g) underwent surgical implantation of the device along theleft tibia, analogous to conventional implants used in children. Threeanimals received a growing device with a degradable ESPGS inner core,and three animals received a fixed-size device with a non-degradablePTFE inner core that would restrict growth, akin to existing surgicalimplants. The right tibia served as an internal control. All animalsunderwent interval micro computed-tomography (CT) imaging of each tibiato assess bone growth.

This study of growth in one dimension required a straight device to liealong the tibia. To create the inner core for the device, a PGSpre-polymer was cured within PTFE tubing for all 86 hours. Devicemanufacturing for the study involved insertion of the 1.8 mm diametercylindrical ESPGS or PTFE inner core into the biaxially braided UHMWPEouter element. The UHMWPE braid had a pitch of 60 ppi, with a 1/1intersecting pattern. Twenty-four fibers were used to construct thebraided outer element, with each fiber being composed of twenty-five 12nm filaments. Two animals received a PTFE (GOR-TEX) braided outerelement for micro-CT imaging. Twelve CV-5 GOR-TEX sutures (W.L. Gore &Associates, Inc.), each 0.256 mm in diameter, were braided in a 1/1intersecting pattern around a 2.1 mm mandrel. After inserting the innercore inside the braided outer element, a polypropylene (PROLENE) suture(Ethicon) was tied to each end of the device; these sutures were used toanchor the device to the bone during surgical implantation.

FIGS. 13A-13G depict various diagrams, photographs and graphs associatedwith the study. FIG. 13A is a cartoon depicting two types of deviceimplants on a growing tibia. The illustration to the right is a growingdevice with a degradable core that enables autonomous device growth andguided tibial growth. The illustration to the left is a fixed-sizedevice with a nondegradable core that results in a fixed-size implantand restricted tibial growth.

FIGS. 13B-13C depict images of the fixed-size device having anondegradable PTFE core. FIG. 13B shows micro-CT images in axial (left)and sagittal (right) cross-section of the fixed-size device at post-opand at 8 weeks after implantation. The images indicate an absence ofdevice growth over an 8-week survival. FIG. 13C is a side-by-sidecomparison of the fixed-size device at implant (left) and explant(right), which demonstrates no significant change in device length(scale bar=5 mm).

FIGS. 13D-E are images of the growing device having a degradable ESPGScore. FIG. 13D shows micro-CT images in axial (left) and sagittal(right) cross-section of the growing device at post-op and at 8 weeksafter implantation. The images indicate the thinning of ESPGS andconcurrent lengthening of the device over an 8-week survival. FIG. 13Eis a side-by-side comparison of the growing device at implant (left) andexplant (right), which shows significant device elongation (scale bar=5mm).

FIG. 13F is a graph comparing growth of the right tibia, the growingdevice left tibia (“ESPGS left”) and the fixed device left tibia (“PTFEleft”). Implantation of the growing (ESPGS) versus fixed-size (PTFE)device led to distinct growth profiles (mean±s.d.). The fixed-sizeimplant caused progressive growth restriction and ultimately growtharrest in the final 4 weeks. The growing implant provided mild growthrestriction during first 4 weeks, but permitted physiologic bone growthin the last 4 weeks. By 8 weeks, the left tibial length with thefixed-size implant was statistically less than the left tibial lengthwith the growing implant and the right tibial length. (*P<0.05,**P<0.005, one-way ANOVA post-hoc Tukey test).

FIG. 13G is a graph comparing predicted growth and observed devicegrowth. For the growing device (ESPGS device), observed device growthwas closely correlated with predicted growth. The growth profile of thefixed-size implant (PTFE device) is shown for comparison. (n=3 animalsper group).

As seen in the graph depicted in FIG. 13F, device behavior translated todistinct tibial growth profiles for the two animal groups when comparedto the contralateral (right) limb. PTFE animals experienced significantand progressive growth restriction. Overall growth was only 20.0% over 8weeks compared with 32.0% growth in the unrestricted, right tibia(p=0.006). There was near arrest of left tibial growth in the final 4weeks of survival: 2.6% left tibial growth in PTFE animals compared to7.1% growth in the unrestricted, right tibia (p=0.01). By the end of thesurvival period, the left tibial length in the PTFE animals wassignificantly shorter than the right tibial length (p=0.004). Thedistinct growth trends in the final 4 weeks suggest that further growthdifferential would have occurred had the animals been survived longer.The latter 4 weeks of the study, in principle, represent a time whendevice removal/exchange would be necessary in a growing child to avoidexcessive growth restriction.

The ESPGS animals, in contrast, experienced continued, guided bonegrowth that followed the physiologic, unrestricted right tibial growthpattern. As seen in FIG. 13F, during the final 4 weeks, when PTFEanimals experienced significant growth restriction, left tibial growthin ESPGS animals was almost identical to right tibial growth (7.3% vs,7.1%, p=0.27), and final tibial length was similar (38.3 mm vs. 39.5 mm,n.s.). Arrest of bone growth was avoided because of autonomous deviceelongation. In principle, this would prevent the need for deviceremoval/exchange in a growing child.

Example 2: Implantable Device Exhibiting Growth in Two Dimensions

In some embodiments, the device can be used to guide growth in twodimensions, e.g. to treat heart defects. In one example, the device wasused as an annuloplasty in a swine study. Curved ESPGS inner core pieceswere created for the study. To create these curved pieces, straightpolymer samples were removed from the PTFE tubing after 42 hours ofcuring. The polymer cylinders were then placed into an appropriateradius of curvature and cured at 155° C. for the remaining 44 hours.This division in curing intervals (42 and 44 hours) was chosen becausesufficient curing within the straight PTFE tubing was required toproduce well-formed polymer cylinders prior to inducing curvature.

Production of autonomously growing annuloplasty devices for the studyinvolved insertion of a curved ESPGS inner core into a long segment ofUHMWPE braided outer element. The braid/ESPGS composite was thenattached to a mounting device for surgical implantation, utilizingpolyglactin 910 (VICRYL) sutures (Ethicon).

FIGS. 14B-14I depict various photographs and a graph associated with thestudy. FIG. 14B is a photograph of a UHMWPE biaxially braided sleeveplaced over a pre-curved cylindrical ESPGS polymer core. FIG. 14C is aphotograph showing the pattern of the biaxially braided sleeve. FIG. 14Dis a photograph of an ex vivo demonstration of ring implantation with enface view of the tricuspid valve. In this example, the growing ring issecured to the valve annulus with a conventional suturing technique usedfor ring implantation in adults. The braided sleeve ends and body of thedevice are secured to annulus. FIG. 14E is a photograph of an en faceview of the freshly explanted tricuspid valve and ring 12 weeks aftersurgery. The photographs show that the ring is intact and integratedinto annular tissue without evidence of thrombus formation ordehiscence. FIG. 14F depicts a cross-section through the explanted ringshowing a collagen layer (indicated by the arrow) that grew over thegrowing device. FIG. 14G depicts photographs of explanted ESPGS samplesshowing erosion at the surface of the polymer. FIG. 14H depictscross-sections through segments of the ring/annulus. Thesecross-sections demonstrate regions of significant of core erosion withring thinning (top) and areas of less significant core erosion with lessring thinning (bottom).

FIG. 14I is a graph of the annular area of the valve at three timepoints during the study: pre-implant, post-implant, and euthanasia. Allanimals experienced valve reduction following ring implantation (leftregion), and experienced valve growth in the post-operative period(right region). Looking to the right-most end of the lines, the top lineis the 12 week animal, the second line down is the 16 week animal, thethird line down is the 5 week animal, and the bottom line is the 20 weekanimal.

In this study, four growing, female Yorkshire piglets (mean age 7.3±0.9weeks) underwent surgical implantation of a growing annuloplasty ring onthe tricuspid valve and were survived for 5, 12, 16, and 20 weeks toassess device behavior and valve growth. The growing annuloplasty devicewas shaped to have a similar geometry to commercially available,fixed-size annuloplasty rings, such as the fixed-size ring shown in FIG.14A. The growing annuloplasty device, shown in FIG. 14B, was designed toreduce valve size at implantation akin to existing rings, and thenexpand to accommodate valve growth. The device included a UHMWPE braidedsleeve over a curved cylindrical ESPGS core. A magnified view of thesleeve's biaxial braid configuration is shown in FIG. 14C. As shown inFIG. 14D, the ends of the braided sleeve were anchored to the valveannulus with sutures, and additional sutures were placed through thevalve annulus and around the ring along its length. This enableddownsizing of the annulus and apposition of the ring to the annulus.

In all cases, the ring remained well-affixed to the valve annulusthroughout the survival periods without evidence of dehiscence, as seenin FIG. 14E. This may have been promoted by the development of acollagen tissue layer over the device following implantation, as seen inFIG. 14F. ESPGS degradation was observed on direct inspection ofexplanted core segments, as seen in FIG. 14G. Cross-sections throughexplanted ring segments demonstrated areas of significant polymer coreerosion following implantation, as seen in the top image of FIG. 14H,although there was regional variation with some segments experiencingless extensive core erosion, as seen in the bottom image of FIG. 14H.

Echocardiographic evaluation showed that the tricuspid valve in eachanimal was effectively downsized by the growing ring prototype at thetime of surgery (see FIG. 14I, pre-implant to post-implant). Thisdemonstrated that the growing ring could withstand intra-cardiac forcesand effectively constrain the valve, as is necessary in heart valverepair surgeries. Valve reduction was then followed by some degree ofvalve growth after device implantation (see FIG. 14I, post-implant toeuthanasia).

As discussed above, in all animals, the ring remained firmly affixed tothe valve annulus throughout the survival period. ESPGS erosion occurredearly in the survival period, as evidenced by the decrease in ESPGSdiameter over the first five weeks. Normal valve growth, which followedBSA growth, was achieved during the first several weeks after ringimplantation, concurrent with when ESPGS was degrading. Beyond 5 weeks,there was minimal change in ESPGS diameter. The resultant fixed size ofthe implant at later survival periods correlated with a slowing of valvegrowth relative to BSA growth. This association between polymerdegradation and valve growth lends support to the fundamentalmechanistic phenomenon observed in the rat model: inner ESPGSdegradation enabled device growth, and tissue growth was accommodated.Conversely, in circumstances of fixed inner polymer size (i.e. anondegradable PTFE inner core in the rat model control group, or slowingof ESPGS degradation in the swine model), the implant did not grow, andtissue growth was restricted.

This study demonstrated the ability of the growing annuloplasty deviceto control heart valve growth.

It should be understood that the foregoing description is intendedmerely to be illustrative thereof and that other embodiments,modifications, and equivalents are within the scope of the presentdisclosure recited in the claims appended hereto. Further, although eachembodiment described above includes certain features, the presentdisclosure is not limited in this respect. Thus, one or more of theabove-described or other features of the implantable device or methodsof use, may be employed singularly or in any suitable combination, asthe present disclosure and the claims are not limited to a specificembodiment.

1. An implantable device, comprising: an outer element having a firstlength; and an inner core disposed within the outer element, whereinpresence of the inner core limits elongation of the outer element,wherein degradation of the inner core permits elongation of the outerelement from the first length to a second length that is longer than thefirst length.
 2. The implantable device of claim 1, wherein the innercore comprises a polymer.
 3. The implantable device of claim 1, whereinthe inner core comprises a biodegradable core.
 4. The implantable deviceof claim 1, wherein the inner core comprises a material that softensover time when placed in contact with body fluids.
 5. The implantabledevice of claim 1, wherein the inner core comprises an erodible metal.6. The implantable device of claim 1, wherein the outer elementcomprises a tubular sleeve.
 7. The implantable device of claim 1,wherein the outer element comprises a braided element.
 8. Theimplantable device of claim 6, wherein the outer element comprises abiaxially braided element.
 9. The implantable device of claim 7, whereinthe outer element has a pitch of 20 to 70 picks per inch.
 10. Theimplantable device of claim 8, wherein the outer element has a pitch of60 picks per inch.
 11. The implantable device of claim 1, wherein thesecond length is 10 to 180 percent greater than the first length. 12.The implantable device of claim 11, wherein the second length is 60 to65 percent greater than the first length.
 13. The implantable device ofclaim 1, wherein the outer element is made ofultra-high-molecular-weight polyethylene.
 14. The implantable device ofclaim 1, wherein the outer element is made of polytetrafluoroethylene.15. The implantable device of claim 1, wherein degradation of the innercore permits the outer element to grow in two dimensions.
 16. Theimplantable device of claim 1, wherein the inner core comprises aplurality of separate pieces.
 17. The implantable device of claim 16,wherein the plurality of pieces are spaced from one another.
 18. Theimplantable device of claim 1, wherein the inner core is formed as asingle piece.
 19. The implantable device of claim 1, wherein the innercore has a curved shape.
 20. The implantable device of claim 1, whereinthe inner core has a cylindrical shape.
 21. The implantable device ofclaim 1, wherein the inner core is made of a modified form ofpoly(glycerol sebacate).
 22. The implantable device of claim 1, whereinthe inner core is a degradable elastomer.
 23. The implantable device ofclaim 22, wherein the degradable elastomer is poly(glycerol sebacate).24. The implantable device of claim 23, wherein the degradable elastomerhas a Young's Modulus that is greater than 5 MPa.
 25. The implantabledevice of claim 22, wherein the degradable elastomer has a Young'sModulus that is greater than 100 MPa.
 26. The implantable device ofclaim 21, wherein the modified form of poly(glycerol sebacate) is formedby curing a poly(glycerol sebacate) pre-polymer at a temperature of over150° C. for over 80 hours.
 27. The implantable device of claim 26,wherein the poly(glycerol sebacate) pre-polymer is cured at atemperature of 155° C. for 86 hours.
 28. The implantable device of claim1, wherein an instantaneous length L of the outer element is defined bythe following equation:L(D)=√{square root over ((πnD _(i))² +L _(i) ²−(πnD)²)} wherein n isbraid pitch as defined by number of fiber turns per unit length, D_(i)is initial element diameter, L_(i) is initial element length, and D isinstantaneous element diameter.
 29. A method of using an implantabledevice, comprising: providing an outer element with an inner coredisposed within the outer element; and coupling the outer element to animplantation site, wherein: contacting the inner core with body fluid atthe implantation site initiates degradation or softening of the polymercore, degradation of the inner core permits elongation of the outerelement from a first length to a second length that is longer than thefirst length, and the length of the outer element changes from the firstlength to the second length in response to degradation of the inner coreand to forces from native growing tissue at the implantation site actingon the outer element.
 30. A method of forming a biodegradable polymer,comprising: polycondensation of an equimolar ratio of glycerol andsebacic acid at 120° C. for 8 hours under dry nitrogen and for 16 hoursin vacuum to form a pre-polymer; and curing the pre-polymer in a vacuumat a temperature of 140° C. to 160° C. for 40 to 100 hours.
 31. Themethod of claim 30, further comprising: putting the pre-polymer in amold.
 32. The method of claim 31, wherein the mold is curved.
 33. Apolymer comprising: a Young's Modulus of greater than 5 MPa; and acrosslinking density of 600 to 12,000 mols per cubic meter, wherein thepolymer is formed from curing a poly(glycerol sebacate) pre-polymer invacuum at a temperature of 140° C. to 160° C. for 40 to 100 hours.